CA2193097C - Synthesis of conduritol epoxides and aziridines and methods of using such to synthesize higher disaccharides - Google Patents

Abstract

There are described novel coupling reactions useful for the preparation of cyclitol and/or carbohydrate conjugates and carbocyclic analogs thereof. Such coupling reactions employ epoxides and/or aziridines described herein as electrophilic recipients of other cyclitol or carbohydrate units. Also provided are certain novel compounds.

Description

2 1 9 3 0 9 7 PcT/U895/0760I

ffiET$ODS OF USING SUCH TO SYNTHESIZE 8IG8ER DISACCAAnTDES
FIELD OF TRE INVENTION
This invention relates to novel processes for the synthesis of certain conduritol epoxides and aziridines and the use of these epoxides and aziridines to synthesize various or higher disaccharides such as conjugates of cyclitols and/or carbohydrates and their carbocyclic analogs (C-analogs), as well as various heteroatom-linked conjugates such as N-, S- or 0-linked conjugates.
This invention also relates to certain novel compounds useful as synthons and/or as therapeutic agents useful in treating various disease in a mammal.

The expression of arene cis-diols was originally discovered and described by Gibson 24 years ago (Gibson, D. T.; Hensley, M.;
Yoshioka, H.; Mabry, J. J. Biochemistry, 1970, 9, 1626). Since that time, use of such arene cis-diols in enantiocontrolled synthesis of oxygenated compounds has gained increasing acceptance by those skilled in the art. Many examples of their applications to the total synthesis of carbohydrates, cyclitols, and oxygenated alkaloids can be found in the literature; however, much of the work done within this area has been with the more traditional approach of attaining optically pure compounds from the carbohydrate chiral pool. (Hanessian, S. in Total Synthesis of Natural Products: The Chiron Approach; Pergamon: Oxford, 1983).

The synthesis of glycoconjugates has attracted considerable attention recently [(a) Borman, S., C&E News 1994, 72, (9), 37; (b) Glycotechnology conference, San Francisco, 1993]. Higher saccharides such as the gangliosides GM3 and sialyl Lewis x both of which are proposed to be involved in malignancy and intercellular adhesion, trans-cell membrane signal transduction and regulation of cell growth have been the subject of intense focus [(a) Danishefsky, S. J.; McClure, K. F.; Randolph, J. T.; Ruggeri, R. B. Science 1993, SUBSTITUTE SHEET (RULE 26) WO 95135303 21Q3O O 7 PCTIUS95/07601 =
260, 1307; (b) Liu,/K. K/./-C.; Danishefsky, S. J. J. Am. Chem. Soc.
1993, 115, 4933] by chemical as well-as enzymatic means [Ichikawa, Y.; Lin, Y.-C.; Dumas, D. P.; Shen, G.-J.; Garcia-Junceda, E.;
Williams, M. A.; Bayer, R.; Ketcham, C.; Walker, L. E.y Paulson, J.
C.; Wong, C.-H. Am. Chem. Soc. 1992, 114, 9283]. The current chemical and/or enzymatic synthesis of these compounds is arduous at best giving rise to a growing body of high yielding, selective, chemical and enzymatic glycosidation methodologies [(a) Raghavan, S.; Kahne, D. A one-step synthesis of the ciclamycin trisaccharide.
J. Am. Chem. Soc., 1993, 115, 1580 and the references therein.; (b) Frazer-Reid, B.; Zugan, W.; Andrews, W.; Skowronski, E. Torsional effects in glycoside reactivity: saccharide couplings mediated by acetate protecting groups. J. Am. Chem. Soc., 1991, 513, 1434.; (c) Frazer-Reid, B. n-Pentenyl glycosides in organic chemistry: a contemporary example of serendipity. Synlett, 1992, 927.; (d) Veeneman, G.H.; van Leeuwen, S.H.; van Boom, J.H. An efficient thioglycoside-mediated formation of a-glycodidic linkages promoted by iodonium dicollidine perchlorate. Tetrahedron Lett., 1990, 31, 274.; (e) Kondo, H.; Achi, S.; Ichikawa, Y.; Halcomb, R.C.; Ritzen, H.; Wong, C.-H. Glycosyl phosphites as glycosidation reagents: scope and mechanism. J. Org. Chem., 1994, 59, 864.; (f) Toshima, K.;
Nozaki, Y.; Inokuchi, H.; Nakata, M.; Tatsuta, K.; Kinoshita, M. A
new entry for the controlled synthesis of 2,6-dideoxy oligosaccharides. Tetrahedron Lett., 1993, 34, 1611]. However, these glycosidation methods are incompatible if the glycosidic donor is to be a carba-sugar and, therefore, would not be useful if a fully carbocyclic oligosaccharide analog were reguired_ Thus, the carbocyclic analogs of these types of compounds are generally unattainable by currently available methods, unless long and arduous routes from carbohydrates are employed [see generally: Hanessian a13=] =

Whereas the carbocyclic analogs of simple sugars are known (Suami, T.; Ogawa, S. In Advances in Carbohydrate Chemistry and Biochemistry; Tipson, R. S.; Horton, D., Eds.; Academic: New York, 1990; Vol. 48, p 21; Ley, S. V.; Yeung, L. L. Synlett 1992, 291) an atternpt at rational and exhaustive design of higher members is absent in the literature. - --The present invention alleviates the problems associated with_prior chemical or enzymatic synthesis for making cyclitol and carbohydrate W O 95135303 2 l 9 3 0 9 7 PCT/US95/07601 conjugates and/or C-analogs thereof by providing methods and useful synthons such as cyclitol conjugates and aziridines which are specifically useful in pseudo-sugar couplings so that semi- and/or fully carba-analogs of carbohydrates can be prepared.

tt2R+iA.RY OF THE INVENPION
Therefore, one aspect of this invention relates to biocatalytic methods of synthesis for various conjugates of cyclitols and carbohydrates and their C-, N-, S- or 0-linked conjugates.
Specifically the conjugates made by the present invention have the formula (1) R1 }
R3 ~-i R6 X~H
~_X OR4 wherein:
X'-X' independently are CHõ 0, NH, or S;
Y is CH2, 0, NH, or S;
Z is CH=, 0, NH, or S;and R1-R6 independently are any alcohol protecting group.

Another aspect of the present invention relates to the synthesis and use of cyclitol epoxide (2) and cyclitol aziridine (3) as electrophilic recipients of other cyclitol or C-sugar units in the coupling reactions described herein. -Cyclitol epoxide (2) has the formula:

c w Ol. OR' wherein:

X' is H, halogen, CN, alkyl (branched or unbranched Cl-C5), aryl (substituted or unsubstituted aromatic) or a heteroatom (wherein the heteroatom may be alone or in a straight chain or ring structure); and each R' is independently any alcohol protecting group;
provided that the alcohols at C2 and C3 need not be protected with the same protecting group.

Aziridine (3) has the formula:

õ

R"
/

.
' OR"

wherein:
X" is H, halogen, CN, alkyl (branched or unbranched Cl-C5), aryl (substituted or unsubstituted aromatic) or a heteroatom (wherein the heteroatom may be alone or in a straight chain or ring structure);

each R" is independently any alcohol protecting group;
provided that the alcohols at C2 and C3 need not be protected with the same protecting group; and R" is H, CBZ, tosyl or any substituted or unsubstituted arylsulfonic acid amide, benzyl or COzMe.

Compound 2, its synthesis, and use as a synthon are described in commonly owned U.S. Patents 5,633,412; 5,606,287; 5,602,263 5,600,014 and 5,578,738. Compound (3) is a novel aziridine and, therefore, another aspect of this invention relates to novel compounds of the formula (3).

DETA3L=ED DESCRrp'1'=nu AF 'P8E IHVENT=n**
The present invention relies on understanding and controlling the sites of potential coupling of electrophiles 2 and 3 with nucleophiles. In the general structure 4 (encompassing such electrophiles), there are three possible pathways to R
~.~.~ R

wherein.:
X=H, Cl, Br, I, F
Y=O, NTs, NCBZ, NH
R=C(CH3)2, C=O, alkyl, acyl open such electrophiles: a, b, and c. Path b is precluded by stereoelectronic effects, whereas path a. and c are subject to normal SN and S. arguments as described in the literature on the chemistry of vinyloxiranes. To date, the opening at sites a or c with carbon nucleophiles has been attained only with acetylide anion [Ley, S.
V.; Yeung, L. L. Synlett 1992, 291-292]. The chemistry of vinylaziridines in general has been limited to their rearrangements to pyrrolines, which involves SN, opening and reclosure with iodide [Hudlicky, T.; Reed, J. W. In Comprehensive Organic Synthesis;
Paquette, L. A., Ed.; Pergamon: Oxford; Vol. 5, Chapter 8.1]. One example of a cuprate addition to vinyl aziridines has been recently reported. [Ibuka, T., et al. Angew. Chem. Int. Ed. Engl., 1994, 33, 652]. The preparation of 3 and its nucleophilic opening tendencies thus remained unknown until the present disclosure.

For the synthesis of glycoconjugates and.,especially their C-analogs that may offer complementary biological activities, it is desirable that the sites a and c be controlled equally well for heteroatom as well as carbon nucleophiles. For the synthesis of higher saccharides it is also desirable that such opening generate only one nucleophilic group at any given time so that it is available for the next reaction.

Thus the present invention describes the initial model studies necessary to establish the regio- and stereocontrol of nucleophilic opening for 2 and 3. From these initial models, cyclitol and conduramine conjugates such as 5, 6, and 7 as well as their further functionalization to compounds such as 8, 9, and 10 have been made WO 95/35303 2I / J U/( PCT/US95l07601 demonstrating that further attachment of protected cyclitol and sugar units is possible in a controlled manner.

?H
~~ ~~

6R Oe 5. X=O 8. X=O

6. X=NTs 9. X=NTs 7. X=NH 10. X=NH
(each R may be Me,Bz,H or (each R may be Me,Bz,H or any other alcohol - any other alcohol protecting group) protecting group) The demonstration of the present invention with regard to the synthesis of compounds 5-10 is merely illustrative of-the present invention. Those skilled in the art will readily understand the implications of this methodology as it relates to preparation of any cyclitol or carbohydrate conjugate. - -In addition, the preparation of fully carbocyclic analogs of the aforementioned compounds (5-10) are described herein,-and their synthesis is envisioned by the present invention.- Synthesis of these fully carbocyclic analogs rely on the coupling of an ---organometallic moiety such as 11, which can be derived from dehydroshikimate 12 (Scheme 1).

rScheme 1 /
~-O OH I.iO'~' /; R 4r 36H OR

OH
JXH R R R
R R
H ]i OI

Li0RO~ OR
OR OR

Scheme 1: (R and X are as defined above for oompound 11 Although the present disclosure outlines model studies and reactivity trends of synthons 2 and 3 toward carbon nucleophiles, it also serves as a stereoelectronic model for the union of heteroatom nucleophiles with compounds 2 or 3 to produce higher saccharides and their C-analogs and various heteroatom-linked conjugates. Compounds such as 13 or its hydroxylated analog 14 (derived by methods disclosed in U.S. Patent No. 5,306,846 and in several publications:
(a) Hudlicky, T.; Reed, J. W. In Advances in Asymmetric Synthesis:
A. Hassner, Ed.; JAI Press: Greenwich, CT, 1994; (b) Hudlicky, T.; Rulin, F.; Tsunoda, T.; Luna, H.; Andersen, C.; Price, J. D. Isr. J. Chem. 1991, 31, 229; (c) Hudlicky, T.; Luna, H.;
Olivo, H. F.; Andersen, C.; Nugent, T.; Price, J. D. J. Chem Soc.
Perkin Trans. 1 1991, 2907] are inaccessible by methods currently employed for the synthesis of higher saccharides. Recent disclosures [(a) Ley, S. V.; Yeung, L. L. Synlett 1992, 997; (b) Reddy, K. K.; Falck, J. R.; Capdevila, J. Tetrahedron Lett. 1993, WO 95l35303 2193097 PCT/U595/07601 34, 7869] indicate that such compounds may be useful as antidiabetic agents and in general cell-signalling mechanisms.
The currently disclosed invention capitalizes on. some of the previously disclosed techniques of operationally simple provision of sugar or cyclitol units from arene cis-diols as is outlined in Scheme 2(see also: (a) Hudlicky, T.; Mandel, M.; Rouden, J.;
Lee, R. S.; Bachmann, B.; Dudding, T.; Yost, K. J.; Merola, J. S.
J. Chem. Soc., Perki.n Trans. 1 1994, 1553; (b) Hudlicky, T.;
Rouden, J.; Luna, H.; Allen, S. J. Am. Chem. Soc. 1994, 116, 5099; (c) Hudlicky, T.; Olivo, H. F.; McKibben, B. J. Am. Chem.
Soc. 1994, 116, 5108] and provides conceptual guide as to the oligomerization of these units as outlined in Scheme 3.

Scheme 2 ~ nn cciscinn -]_ .6 ~ iccion OH
X=OH, Y=NR2 closure a HO OH X OH X=NR2, Y=OR HpN OH
NHZ y OH
16 15 lg aminocyclitols R=C1,Br amino sugars H
H R c OH
OH b OH Y
~ C1- b sciscinn ('i_['(~ crission OH
closure b closuie c OH X=NR2, Y=OR X OH X-OH, Y=OH,NRZ OH
HO OH y OH
17 1-+ 19 aza sugars R=C1,Br carbohydrates (Y=O) or aza sugars (Y=NH) SUBSTITUTE SHEET (RU! E 26) = WO 95135303 219 3 0 9 7 pCTI13S95/07601 Scheme 3 OH
or 2 or 3 ~ ~z 2 ar 3 etc ~-X-~
~-NHZ

or nucleopbile nucleophile %=0,N++fCH2 Scheme 3 illustrates in a very simplistic manner the overall impact of the present invention, whereby electrophiles such as 2 and 3 are opened at controlled sites, by heteroatom or carbon nucleophiles (under appropriate conditions) resulting in the coupling of the electrophile (conduritol epoxide or aziridine 2 or 3) with the heteroatom or carbon atom which newly coupled nucleophile can repeatedly be coupled with similar electrophiles resulting ultimately in any number of carbohydrates or glycoconjugates.

Of additional significance in the current invention is the stepwise control of introduction of substituents made possible by differential protection as well as stereoelectronic differences between olefins in the cyclitol units. In other words, when protecting the electrophile with different groups and protecting the nucleophile with different groups, only one nucleophilic and electrophilic site will be available at a time. For example, as shown in Scheme 4, opening epoxide 20 with benzyl alcohol affords cyclitol 21 which is now disposed to act_as a nucleophile when exposed to epoxide 22._ gftercoupling 21 and 22 there is only one hydroxyl in 23 and two olefins, which can be successfully functionalized to either cis or trans protected diols by methods disclosed in U.S. Patent No. 5,306,846;
Hudlicky, T.; Reed, J. W. In Advances in Asymmetric Synthesiss A. Hassner, Ed.; JAI Press:
Greenwich, CT, 1994. For the synthesis of further conjugates this process may be repeated provided only one nucleophilic entity is present.

Scheme 4 etc.
= Bn O
O' ' OH 21 x~

X-o,IVTs ~
~

Further studies indicate that a methylcyclohexyl moiety can be effectively added to, with both epoxides and aziridines, to provide models for C-saccharide conjugates of the type shown below. This concept has been demonstrated by the synthesis of gala-quercitol-L-chiro-inositol conjugate starting from aromatic precursors, such as by Scheme 5 shown below.

WO 95/35303 PCTlU595/07601 OH
i H
PNU OH

OH, NH2, N3 Y ~ 0, NTs Reaction between the epoxide (Carless, H.A.J., Tetrahedon Lett., 1993, 33, 6379) and the secondary alcohol (Hudlicky, T.; Luna, H.;
Olivo, H.H.; Anderson, C.; Nugent, T.; Price, J.D.; J. Chem. Soc.
Perkin' Trans. 1, 1991, 2907; Hudlicky, T.; Mandel, M.; Rouden, J.;
Lee, R.S.; Bachmann, B.; Dudding, T.; Yost, K.J.; Merola, J.S.; J.
Chem. Soc. Perkin Trans. 1, 1994, 1553) both readily accessible=from halobenzenes via microbial oxidation ((a) Gibson, D.T.; Koch, G.R.;
Kallio, R.E.; Biochemistry; 1968, 7, 2653 (b) Gibson, D.T.; Hensley, M.; Yoshioka, H.; Mabry, J.J.; Biochemistry, 1970, 9, 1626)gave in the presence of boron trifluoride, the coupled adduct in 75% yield (Scheme 5). Predominant reaction of the vinyl epoxide at the allylic position follows,observations in our laboratories;
(a) Hudlicky, T.; Konigsberger, K.; Xinrong, T.; J. Org. Chem. 1994, 59, 4037 (b) Hudlicky, T.;
Rouden, J.; Luna, H.; Allen, S.; J. Am. Chem. Soc., 1994, 116, 5099) which indicate the general preference for nucleophiles to attack the allylic position of substrates such as the vinyl epoxide syn to the isopropylidene group. Treatment of the di-alkene (of Scheme 5) with osmium tetroxide, continuously recycled by 4-methyl morpholine N-oxide, gave the bis-hydroxylated species in good yield, which was subsequently converted to the polyoxygenated conjugate (gala-quercitol-L-chiro-inositol) under acidic catalysis.

Scheme 5 O
0x OH c:x BF3Et2O, CH2C12 75%
Os04, NMO, ItO, acetone, t-BuOH
74%
OH
OH OH ci3Zx HO~ Amberlyst resin HO O : OH
MeOH, H20 O
OH
HO OH 98% HO,,,.,,,1OH
OH
bH A~_o *,, e current invention facilitates the design and synthesis ofmany Th higher cyclitol conjugates and their,_C-analogs unavailable by_ traditional methods. The combinational possibilities regarding substitution patterns, identity of protecting groups, stereochemistry and enantiomeric constitution are well understood to those skilled in the art. These parameters can be controlled at the stage of each monomeric unit.

--,PVp 95135308 2 1 9 3 U9.7 PCT/US95/07601 As used in the present invention "suitable or appropriate solvents"
include, but are not limited to, water, water miscible-solvents such as dialkylketones with 2-4 carbon atoms, lower alcohols having 1-3 carbon atoms, cyclic ethers, and ethers with 2-6 carbon atoms, or mixtures thereof.

As used herein "reducing agent" includes, but is not limited to, a transition metal reagent, a hydride reagent or trialkylsilane such as tributyltinhydride or tris(trimethylsilyl) silane, sodium naphthalide, or sodium amalgam. These reducing agents may be used in combination with radical initiation agents such as UV light and/or AIBN or dibenzoylperoxide or a similar initiator.

As used herein"acid catalyst" includes, but is not limited to, mineral acids such as HC1; Lewis acids; organic acids such as p-toluenesulfonic acid; acid ion exchange resins such as Amberlyst 15, Amberlyst IR 118, Amberlite CG-50, Dowex 50 X 8-100 (all are commercially available from Aldrich), or similar acidic ion exchange resins.

As used herein "alkaline catalyst" includes, but is not limited to, alkaline metal hydroxide or alkaline earth metal hydroxides such as LiOH, NaOH, KOH, or Ba(OH)z; carbonate or bicarbonate of alkaline metal stich as Na2CO3 or K~C03; Alz0; or basic ion exchange resin such as Amberlite IRA-400, Amberlyst A26, Amberlyst A21, Dowex lX2-200 or other ion exchange resins.

As used herein "an alcohol protecting group" includes, but is not limited to, H, acetate, acetonide, alkyl (C1-C5), aryl (any aromatic group substituted or unsubstituted), esters, ethers, silylethers, arylsulfonylamides, t-butyldimethylsilyl, benzyl, benzoates or any other alcohol protecting group known to those skilled in the art.

As used herein "an appropriate organometallic reagent" includes, but is not limited to, those described in Tables 1 and 2. Such reagents are commonly known to those skilled in the art. These are shown in Table 1 by the general formula RM where R is methyl, methylcyclohexyl, or phenyl, and M is Mg, Cu, Sn, Pd.

As used herein "carbon or heteroatom conjugate" means a C-, N-, 0- or S-linked conjugate or analog of a given compound, such as a C-, N-, 0- or S-linked analog of cyclitols and/or carbohydrates.
Suitable conditions, including solvents and temperatures are listed in Tables 1 and 2 and include, but are not limited to, the types of solvents and temperature ranges respectively. Temperature ranges implies -100 C to +160 C.

General Svnthesis of .l roDhil 2 and 3 Epoxide 2 and aziridine 3 can-be-generated following the biocatalytic production of r1C-diolsderived from substituted benzenes. However, the coupling methods of the present invention will work regardless of the method used to make the electrophiles 2 and 3. The synthesis of epoxide 2 is described in U.S. Patent 5,306,846 and U.S. Patent Application No. 07/974,057, the disclosure of each is incorporated herein by reference; and Hudlicky, T., Rulin, F., Tsunoda, T., Luna, H., Andersen, C., Price, J. D. isr. J.
Chem. 1991, 31, 229. The aziridine is a novel compound and its synthesis is described both generally and in detail in the Experimental section herein. General methods for aziridine formation are found in Yamada, Y., Yamamoto, T., Okawara, M. Chem.
Lett. 1975, 361; Evans, D. A., Paul, M. M., Bilodeau, M. T. J. Org.
Chem. 1991, 56, 6744; and Evans, D. A., Faul, M. M., Bilodeau, M.
T., Anderson, B. A., Barnes, D. M. J. Am. Chem. Soc. 1993, 115, 5326.

Use of Svnthons 2 and 3 Compounds such as 14, 23 and 24 are generated by exposing either epoxide 2 or aziridine 3 to nucleophilic monomers such as 11 derived from dehydroshikimate. These initial targets are identified and fully deprotected to obtain corresponding compounds containing all free hydroxyl or aminogroups. These compounds may be used in the treatment of diabetes or other cell-signalling mediated diseases.
Partially protected dimers such as 14, 23 and 24 may then be used in further coupling to generate trimers_which can subsequently be coupled to form tetramers, etc. The details of methods available-for the coupling of sugars or cyclitol monomers are providedbelow.

WO 95135303 219 3 0 9 7 pC1'/t3S95/07601 Table 1 lists the major products obtained thus far by opening of epoxides 2a and 2b with organometallic reagents of the general formula RM where R is methyl, methylcyclohexyl, or phenyl, and M is Mg, Cu, Sn, Pd. The Table is not intended to limit the present invention, particularly since these reactions are disclosed to serve as model systems for C-disaccharide synthesis, as, for example, opening of an epoxide (2a) with methyl organometallics to yield 25.
Compound 25 can be used for the synthesis of methylquercitol (deoxy-C-mannose) derivative 45 as shown below.

OH
H OH
x 1. Na/NI33_ 2. mCPBA
000, 3. H3O* OH
OH OH

By the same token, the use of methylcyclohexyl residues provides C-disaccharide model Compound 46 by the reaction shown below:
OH
X H OH
1. Na/NIiz 2, mCPBAor 0804 eOH 3. H30* OH
OH

Further application of the coupling methods of this invention is illustrated by the reaction below showing an azido or amino derivative of 46, namely 47 and 48 respectively, available from 26 by the sequences shown:

WO 95/33303 YC'T/US95/07601 ~ OH OH
O \ ' _ N3 R H2N
/~v' 1. Na/NH3 1. LiA1Hg 2. mCPHA 2. H
O 3. NaN3/1YUE R
H
bH O Lm 26 c 47a R-C(CH3) a H30 + =47b R-H-A trisaccharide can be made by the coupling methods, described_ herein, for example, 49 is available from 27 by full deprotection.
It should be noted that isomers 32 and 33 (shown in Table 1) are ideally suited as disaccharide models also, albeit in different configurations than the C-mannose 44. -1=Hz ~ H
OX
bH H
;
OH

(R-cyalobexylmethyl) Table 2 lists the major products obtained thus far byopening aziridines 3a and 3b. Table 2 is not intended to limit the present invention, particularly since these-reactions are provided as a model system for coupling reactions. One skilled in the art will recognize various embodiments of the present invention such as those described herein.

WO 95135303 2 1 9 3 0 9 7 PLy.IEJg95/07601 Aminoinositol compounds of the type 50 are accessible as shown in the examples below:

HO H
\ / 1. Na/NH
/J~' 2. mCPBA
3. H30' H
ISHTs AH2 Phenyl (CuCN) cuprate was used to form product 43 in an improved yield of 49%. It is contemplated that using the methods of the present invention the compound pancratistatin 53, a known anticancer agent, can be made from the known compound 51 (C.H. Heathcock, et al. Tetrahedron Lett., 1992, 6775) based on the conversion of compound 51 to 52 as shown.

O
O~ ~ q 2b (CuCN)/THF/BTj ph CONE42 IVHTs OR

OH
X H OH
OH
NHTs NMH
CON&2 OH O

It is further contemplated that the coupling methods described herein can be employed in pseudo-sugar coupling such that semi- or fully carba-analogs of the general type 55 or 57 or other heteroatom conjugates of 54 and 56 could be made.

OH

OH
HO X X X NHCO(CH2)16Me AcNH O (CH2)16Me HO HO HO
OH OH
OH 54. X = 0 GM3 55. X = CH2 OH
HO X X
X
AcNH
HO HO X
Me x NHAc OH
OH 56. X= O Sialy! Lewis x OH 57. X = CH2 HO
The ganglioside GM3 54 and its metabolic precursors are important starting points for the biosynthesis of other gangliosides.
Gangliosides in general have been proposed as being involved in malignancy and intercellular adhesion, trans-cell membrane signal transduction and regulation of cell growth. GM3 itself is known to be active in governing epidermal growth factor and platelet-derived growth factor receptors, and importantly is found in much higher concentrations in tumor cells. Sialyl Lewis x 56 is an important cellular surface oligosaccharide involved in cellular adhesion processes and also found in increased amounts in patients suffering from breast, pancreatic and gastrointestinal cancer. The interest in these two structurally similar oligosaccharides has stimulated several chemical and enzymatic total syntheses.

For these reasons there should be great interest in the synthesis of carba-oligosaccharide analogs of GM3 or sialyl Lewis x. We propose that access to these types of semi- or fully-carbocyclic mimics should be attainable by coupling nucleophilic carba-sugars with standard glycosidic donors or electrophilic carba-sugar epoxides and aziridines.

SUBSTITUTE SHEET (RULE 26) = prO 95133303 2 1 9 3 0 9 7 PCT/US95107601 The precise choice of 0-atom replacement within GM3 (see 55 above) will await the synthesis of the first such derivative containing 0-linked carba-sugars and its biological evaluation. Following this result, rational thought and design will be applied to the definition of the next specific target. We believe that the demonstration of the capability to synthesize such carba-analogs in a controlled manner will open the way for the preparation of any isomer or isostere of these and other saccharides.

Exemplary reactions for vinyloxiranines and vinylaziridines are shown in Tables 1 and 2 respectfully. It is understood that the skilled artisan, reading this disclosure will be able to alter the exact electrophile, nucleophile, and conditions of the reactions.
Therefore, these are provided to illustrate the present invention and should not be construed as limiting the invention.

=

TABLE 1. EXEMPLARY REACTIONS OF VINYLOXIRANES
ELECTROPHILE NUCLEOPHILE/ PRODUCT
CONDITIONS ($ YIELD) MeMgBr/10% Cui THF/-78 to -40 C
X H X
bH
2a 25 ss RMgBr/10% CuI
THF/-78 to 0 C

X R=cyclohexylmethyl v /\
OH
2a 26 (39) R2CuLi Et2O/THF/-78 to -40 C

X R=cyclohexylmethyl R= x p " OH oa 2a 27 (14) xe (s) Ph2CuLi Et20/0 C
X ~x -OH
2a 29 (E) MeMgBr/10% CuI
EtzO/THF
(:CNA
~X
~ CIR aff 2b 30 (33) 31(11) WO 95/35303 219309' PCT/US95/07601 ELECTROPHILE NUCLEOPHILE/ PRODUCT
CONDITIONS ($ YIELD) RMgBr/10% CuI
THF/-78 to -10 C R
> < R=cyclohexylmethyl 2b OH
32 (83) RzCUI,i IIII>< EtzO/THB/-78 R
to -40 C

R=cyclohexylmethyl O" vv ~~oo OEI OB
2b 33(37) 34(3) Me2CuLi Et=O/THF/-780C
~ H3C p><
O
2b OH
35(30) PhSnMe3/Pd(0) ~ DMF/Hz0/RT ~~
/
PL
O"
2b OH
36 (10) WO 95/35303 PCalUS95107601 TABLE 2. p'Xp=MPLARY REACTIONS OF VINYLAZIRIDINES
ELECTROPHILE NUCLEOPHILE/ PRODUCT
CONDITIONS ($ YIELD) PhZCuLi _ THF/-78 C to RT
oX
T&N NHTs 3a 37 (57) PhzCd o>< x TsN NRTs 3a 38(50) Ph2Zn THF/Et20/RT
eb 0 NHTi tlHrS
T~ 37 3.1(36) 38 R2CuLi THF/Et2O/-78 to -40 C

X R=cyclohexylmethyl O/ \ R
T~ NHTs 3a 39(89) CH3MgBr/CuI
THF/Et20/-45 C
O><
TsIV NHTe 3a 40(53) ELECTROPHILE NUCLEOPHILE/ PRODUCT
CONDITIONS YIELD) RzCuLi Et2O/THF/-78 R
to -40 C

>< R=cyclohexylmethyl O V b TsN
3b NHTs 41(76) Ph2CuLi THF/-78 to RT Ph ~~y + ~~
TSN NH7s l7FYfs 3b 42 (38) 43(6) PhZCuCNLi3 Pkl~
TsN ~
3b ~s 43 (23) CH3MgBr/CuI -THF/Et20/-45 C
/
~ H ~
o TsN NfiTs 3b 44 (29) 9!Y9F.RTMFT1TaT.
General: All reactions were carried out in an argon atmosphere with standard techniques for,the exclusion of air and moisture.
Glassware used for moisture sensitive reactions was flame dried under vacuum. Tetrahydrofurane, diethylether (ether) and toluene were distilled from Na benzophenone ketyl. 'H NMR spectra were recorded at 270 MHz or 400 MHz, 19C NMR spectra at 50 MHz, 68 MHz or 100.6 MHz. Flash column chromatography was performed on Merck silica gel (grade 60, 230-400 mesh). Elemental analysis was performed by Atlantic Microlabs, Norcross, GA.

General procedure for the formation of aziridines 3a and 3c: A
mixture of 5 equivalents (eq.) of (1S,2S)-3-halo-l,2-isopropylidenedioxycyclohexa-3,5-diene, 1 eq. of p- -tosyliminophenyliodinane (Phi=NTs) and 0.08 eq. of copper acetyl acetonate (Cu(acac)2) in 10 mL mmol'1 of CH;CN was stirred at room temperature (rt). After consumption of PhI=NTs the mixture was filtered through a pad of silica gel and concentrated in vacuo. The crude product was recrystallized from hexane/ethyl acetate. -Examole 1 (1R,48,58,6R)-3-Chloro-4,5-isopropylidenedioxy-7-(41-methyl-phenyl)sulfonylbicyclo[4.1.0]hept-2-ene (3a): The compound was obtained in 20.5% yield from (1S,2S)-3-chloro-l,2-isopropylidenedioxycyclohexa-3,5-diene following the general procedure set forth above (reaction time 18 h): white solid; mp 202-203 C (hexane, ethyl acetate) ; [a]p2 -75.5 (c=1.54, CHC13): 'H NMR
(270 MHz, CDC13) 6 7.82(dm, J=8.2 Hz, 2H), 7.37(dm, J=8.2 Hz, 2H), 6.09 (dd, J=4.9, 1.2 Hz, 1H), 4.65 (ddd, J=6.6, 1.8, 0.7 Hz, 1H), 4.30 (dd, J=6.6, 1.0 Hz, 1H), 3.44 (dd, J=6.5, 1.8 Hz, 1H), 3.34 (dt, J=0.6, 6.5 Hz, 1H), 2.46 (s, 3H), 1.41 (s, 3H), 1.38 (s, 3H);
13C NMR (68 MHz, CDC1,) 6 145.3 (C), 138.06 (C), 134.41 (C),130.06 (2CH), 128.07 (2CH), 119.96 (CH), 111.72 (C), 73.04 (CH), 71.68 (CH), 37.17 (CH), 36.74 (CH), 27.51 (CH3), 26.07 (CHO, 21.74 (CH3);
MS (CI+) m/z (rel. intensity) 356 (M+H') (3), 340 (6), 298 (27),.262 (23), 200 (36), 155 (100), 142 (36), 114 (60), 91 (43). Anal. Calcd.
for C1sH18C1N04: C, 54.00; H, 5.12; N, 3.94. Found: C, 53.92; H, 5.12; N, 3.86. -=le 2 (1R,4R,58,6R)-3-Bromo-4,5-isopropylidenedioxy-7-(41-methylphenyl)-sulfonylbicyclo[4.1.0]hept-2-ene (3c): From 10.52 g (45.52 mmol) of (1S,2S)-3-bromo-1,2-isopropylidenedioxycyclohexa-3,5-diene, 3c (1.97 g, 54% yield) was obtained following the general procedure described above (reaction time 1 h) : white solid; mp 206-207 C (hexane, ethyl acetate); [a]D'S -33.7 (c=1.05 CHC13); 1H NMH (270 MHz, CDC13) 6 7.82 (dm, J=8.2 Hz, 2H), 7.37 (dm, J=8.2 Hz, 2H), 6.35 (dd, J=4.9, 1.3 Hz, iH), 4.64 (ddd, J=6.5, 1.7, 0.6 Hz, 1H), 4.34 (dd, J=6.5, 1.2 Hz, 1H), 3.44 (dd, J=6.5, 1.8 Hz, 1H), 3.28 (dd, J=6.5, 5.1 Hz, 1H), 2.46 (s, 3H), 1.42 (s, 3H), 1.38 (s, 3H); "C NMft(100.6 MHz, CDC13) 6 145.1 (C), 134.1 (C), 129.92 (2CH), 129.89 (C), 127.9 (2CH), 123.9 (CH), 111.5 (C), 73.8 (CH), 71.4 (CH), 37.4 (CH), 36.4 (CH), 27.4 'WO 95/35303 PG7/US95/07601 (CH3), 26.1 (CH3), 21.6 (CH3); MS (CI+) m/z (rel. intensity) 400 (M+H') (2), 384 (1.5), 372 (1.5), 344 (23), 314 (12), 262 (29), 244 (11), 228 (7), 187 (29), 155 (100), 108 (60), 91 (31); HRMS (Cl+) m/z calcd for (C16H18BrNOaS+H) 400.0218, found 400.0231.

Examole 3 1R,4R,55,6R)-4,5-SSopropylidenediosq.-7-(41-methylphenyl) sulfonylbicyclo[4.1.0]hept-2-ene (3b): A mixture of 617 mg (1.54 mmol) of 3c, 896 mg (3.09 mmol) of tributyltin hydride and 23 mg of AIBN in25 mL of toluene was stirred under reflux. After 3 h, another 20 mg of AIBN was added and reflux was continued for 2.5 h.
The mixture was washed with excess saturated KF aqueous solution, and the organic layer was dried over Na'SO4. Removal of solvent and column chromatography (silica gel, 3:1 hexane/EtOAc) afforded 288 mg (58%) of 3b: white solid; 'H NMR (270 MHz, CDC13) 6 7.82 (din, J=8.2 Hz, 2H),7.35 (br.d, J=8.0 Hz, 2H), 5.95 (ddd, J=10.2, 4.4, 1.7 Hz, 1H), 5.76 (dd, J=10.2, 2.4 Hz, 1H), 4.54 (dd, J=6.7, 1.5 Hz, 1H), 4.39 (dt, J=6.7, 1.0 Hz, 1H), 3.37 (dd, J=6.5, 1.8 Hz, 1H), 3.27 (dd, J=6.5, 4.7 Hz, 1H), 2.46 (s, 3H), 1.37 (s, 3H), 1.34 (s, 3H);
1DC NMR (68 MHz, CDC13) 6 144.8, 134.6, 132.4, 129.8 (2C), 127.9 (2C), 120.9 110.7, 70.6, 69.3, 36.4, 35.5, 27.8, 26.1, 21.6.
Examnle 4 (1R,2S,58,68)-4-Chloro-5,6-isopropylidenediozy-2-methylcyclohex-3-en-l-ol (25): 0.65 mL (1.95 mmol) of 3 M methylmagnesium bromide in ether was added to a suspension of 39 mg (0.20 mmol) of CuI in 7 mL
of ether at -40 C. The mixture was stirred for 15 min before it was cooled to -78 C. A solution of 307 mg (1.52 mmol) of 2a in 3 mL of ether was added and the mixture was stirred at -78 C for 2.5 h, then warmed slowly to -40 C. After 2 h, the reaction was quenched with 3 mL of saturated ammonium chloride solution, and the reaction mixture was extracted with ether (3x20 mL). The combined ether layers were dried over Na=SO4, and concentrated in vacuo. The residue was chromatographed on silica gel, eluted with 2:1 hexane/ethyl acetate to afford 293 mg (58%) of 25: colorless oil; bp 100-110 C (0.1 mm, Kugelrohr); [a]ps -21 (c=1.74, CHC13) ; IR (neat) 3460, 2990 2930, 2880, 1375, 1240, 1210, 1160, 1080, 1065, 1050, 925, 870 cm'1; iH NMR
(270 MHz, CDC13) 6 5.79 (d, J=2.0 Hz, 1H), 4.60 (dd, J=6.4, 1.4 Hz, 1H), 4.05 (dd, J=8.9, 6.3 Hz, 1H), 3.34 (dt, J=1.8, 9.0 Hz, 1H), 2.55 (d, J=2.3 Hz, 1H), 2.26 (m, 1H), 1.57 (s, 3H), 1.45 (s, 3H), 1.18 (d, J=7.1 Hz, 3H); 1'C NMR (68 MHz, CDC13) 6 145.3 (C), 138.06 (C), 134.41 (C), 130.06(2CH), 128.07 (2CH), 119.96 (CH), 111.72 (C), 73.04 (CH), 71.68 (CH), 37.17 (CH), 36.74 (CH), 27.51 (CH3), 26.07 (CH3), 21.74 (CH3); MS (EI, 70 eV) m/z (rel. intensity) 203 (M'-CH3) (100), 143 (87), 115 (81), 79 (54)t HRMS (CI+) m/z calcd for (C10H15C103 + H) 219.0788, found 219.0794.

Example 5 -(iR,28,55,68)-(4-Chloro-5,6-isopropylidenedioxy-2-cyclohexylmethyicyclohex-3-en-l-ol (26): To a suspension of 364 mg (14.97,mmo1) of Mg and a small, crystal of iodine in 3 mL of THF a solution of 1_6 mL of cyclohexylmethyl bromide in 15 mL of THF was added over 1 h and the mixture was stirred at rt for 1.5 h. The resulting Grignard reagent was added into a suspension of 160 mg (0.84 mmol) of CuI in 4 mL of THF at -40 C. The mixture was stirred for 15 min, then cooled to -78 C, and a solution of 1.707 g (8.42 mmol) of 2a in 8 mL of THF was added dropwise. The reaction mixture was warmed slowly to 0 C and stirred at 0 C for 3 h. The reaction was quenched with 5 mL of saturated NH4Cl solution and the mixture was extracted with ethyl acetate (3x15 mL). The combined organic layers were dried over-NaaSO,. Evaporation of the solvent and -chromatography (hexane/EtOAc) afforded 995 mg (39%) of-26.

'H NMR (270 MHz, CDC13)6 5.91 (d, J=2.10 Hz, 1H), 4.59 (dd, J
=6.28,1.24 Hz, 1H), 4.05(dd, J =8.59, 6.30 Hz, 1H), 3.38 (dt, J
=8.80, 2.84 Hz, 1H), 2.28 (bs, 1H), 2.24 (m, 1H), 1.53 (s, 3H), 1.42 (s, 3H), 0.70-1.90 (m, 13H). 13C NMR (68 MHz, CDC13) b 131.41 (CH), 127.75 (C), 110.34 (C), 79.91 (CH), 75.89 (CH), 72.97 (CH), 38.64 (CH), 38.39 (CH2), 34.73 (CH), 34.43 (CH2), 32.50 (CH2), 28.29-(CH3), 26.56 (CH2), 26.31 (CH=), 26.12 (CHz), 25.99 (CH3).

Examole 6 -(1R,2R,5R,68)-2,4-Di(cyclohexylmethyl)-5,6-isopropylidenedioxy-cyclohex-3-en-l-ol (27): To a suspension of 215 mg (31 mmol) of lithium in 12 mL of THF at -30 C was added--0.865 mL (6.2 mmol) of cyclohexylmethyl bromide at -30 C. The mixture was stirred 2 h before it was cannulated to a suspension of 590 mg (3.10 mmol) of cuprous iodide in 3 mL of ether precooled to -35 C. The mixture was stirred at -40 C for 40 min and cooled to -78 C, and a solution of 203 mg (1.00 mmol) of 2a in 3 mL of THF was added. The resulting mixture was stirred at -78 C for 2 h and then allowed to warm up to -40 C before the reaction was quenched with 5 mL of saturated @VO 95/35303 PCT/0S95/07601 aqueous NH4C1 solution. The aqueous layer was extracted with ethyl acetate (3x10 mL), and the combined organic phases were dried over S+Ia,SO,. Removal of solvent and flash column chromatography (silica gel, hexane/ethyl acetate, 4:1) afforded 52 mg (14%) of 27 and 12 mg (4%) of 28.

For 27, 'H NMR (270 MHz, CDC11) 6 5.35 (d, J =3.55 Hz,1H), 4.47 (d, J=6.09 Hz, 1H), 4.24 (t, J =6.15 Hz, 1H), 3.90 (bs, 1H), 2.52 (bs, 1H), 2.19 (dd, J=13.96, 5.40 Hz, 1H), 1.41 (s, 3H), 1.39 (s, 3H).
''C NMR (68 MHz, CDC13) 6 134.32 (C), 127.94 (CH), 108.85 (C), 76.51 (CH), 73.96 (CH), 71.05 (CH), 41.99 (CHz), 38.02 (CH2) , 35.29 (CH), 34.98 (CH), 34.99 (CH), 33.87 (CH=), 33.25 (CHa), 32.81 (CH2), 27.73 (CH3), 26.62 (2CH2), 26.32 (2CH2) , 25.94 (CH3).

Examnle 7 (iR,5R,6S)-5,6-Iropropylidenedioxy-4,4-diphenylcyclohex-2-en-l-ol (29): To a suspension of 596 mg (3.12 mmol) of CuI in 5 mL of ether was added 3.5 mL of 1.8 M phenyllithium solution at 0 C. The mixture was stirred for 30 min and then a solution of 634 mg (3.13 mmol) of 2a in 5 mL of ether was added. The mixture was stirred at 0 C for 2 h and at rt for 8 h before the reaction was quenched with mL of ice water. The aqueous layer was extracted with ethyl acetate (3x15 mL), and the combined organic layers were dried over Ma,zSOd. Removal of solvent and column chromatography (silica gel, 2:1 hexane/ethyl acetate) gave 80 mg (8% yield) of 29.

1H NMR (270 MHz, CDC13) 6 7.10-7.40 (m, 10H), 6.38 (d, J =9.93 Hz, 1H), 6.11 (dd, J =9.93,3.59 Hz, 1H), 5.01 (d, J =6.75 Hz, 1H), 4.41 (dd, J=6.77,3.74 Hz, 1H), 4.29 (m, 1H), 1.93 (d, J=6.75 Hz, 1H), 1.36 (s, 3H), 1.27 (s, 3H). 13C NMR (68 MHz, CDC13) 6 147.77 (c), 143.43 (C), 136.12 (CH), 129.86 (CH), 129.49 (2CH), 128.56 (2CH), 127.69 (CH), 127.50 (2CH), 126.64 (CH), 126.20 (CH), 108,79 (C), 81.05 (CH), 79.90 (CH), 69.70 (CH), 52.39 (C), 26.62 (CH;), 25.14 (CH3) .

ExamDle 8 (1R,2S,5R,6S)-5,6-Isopropylidenedioxy-4-methylcyclohex-3-en-1-o1 (30) and (1R,2S,SR,6S)-5,6-Zsopropylidenedioxy-2-methylcyclohex-3-en-l-ol (31): To a suspension of CuI (29 mg, 0.15 mmol) in anhydrous ether was added a solution of methylmagnesium bromide (MeMgBr) (0.515 mL, 1.54 II~nol) at -40 C and stirred for 30 min. At WO 95/35303 2193097 PCT/US95l07601 -78 C compound 2b (200 mg, 1.19 mmol) in anhydrous THF (5 mL) was added precooled via cannula and the mixture was wanned slowly to -40 C and stirred for 2 h at -40 C. MeMgBr (0.25 mL, 0.75 mmol) was added. After 30 min the white suspension was quenched using saturated NH4C1 solution (20 mL) and the mixture was extracted with CH2C12 (4x). The combined organic phases were washed with brine, dried over Na1SOd and concentrated in vacuo. Chromatography (toluene/ethyl acetate, 75:25) afforded 30 (77 mg, 35%) and 31 (24 mg, 118).

30: colorless oil; 'H NMR (270 MHz, CDC13) d 5.75 (ddd, J=9.7, 3.0, 2.2 Hz, 1H), 5.50 (dt, J=9.6, 2.9 Hz, 1H), 4.20 (m, 1H), 4.00 (dd, J=7.8, 6.2 Hz, 1H), 3.81 (t, J=7.3 Hz, 1H), 2.76 (br.s, 1H), 21.7 (m, IH), 1.48 (s, 3H), 1.36 (s, 3H), 1.24 (d, J=7.2, 1H); 13C NMR (68 MHz, CDC13) S 131.89, 130.74, 108.88; 81.44, 79.35, 71.90, 35.12, 27.26, 24.75, 18.91.

31: colorless oil; 'H NMR (270 MHz, CDC13) d 5.80 (ddd, J=9.8, 3.5, 2.8 Hz, 1H), 5.65 (br.d, J=9.8 Hz, 1H), 4.57 (m, 1H), 3.96 (dd, J=9.0, 6.3 Hz, 1H), 3.27 (dt, J=2.6, 9.3 Hz, 1H), 2.73 (d, J=2.4 Hz, 1H), 2.13 (m, 1H), 1.48 (s, 3H), 1.37 (s, 3H), 1.14 (d, J=7.1, 1H);
13C NMR (68 MHz, CDC13) b 136.8, 122-4, 109_4, 79.7, 75.3, 72.8, 35.6, 28.4, 25.8, 17.1.

Rxamnl. e 9 (1R,4S,SR,6S)-4-Cyclohexylmethyl-5,6-isopropylidenedioxrycyclohex-2-an-l-ol (32): To a suspension of 39 mg (0.20 mmol) of cuprous iodide in 3 mL of THF cooled to -40 C was added 2.69 mmol of cyclohexylmethyl magnesium bromide. The mixture was stirred at -40 C for 15 min then cooled to -78 C, when solution of 334 mg (1.99 mmol) of 2b in 4 mL of THF was added. The mixture was warmed to -C with stirring before the reaction was quenched with 5 mL of saturated NH4C1 solution. The aqueous layer was extracted with ethyl acetate (3x15 mL), and the combined organic layers were dried over NazSO4. The product was purified using column chromatography (silica gel, hexane/ethyl acetate, 3:1) to give 439 mg (83%) of 32.
'H NMR (270 MHz, CDC13) 6 5.76 (dt, J=9.71,2.57 Hz, 1H), 5.61 (dt, J
=9.71, 2.77 Hz, 1H), 4.21 (m, 1H), 3.97 (dd, J=7.66,6.08 Hz, 1H), 3.83 (dd, J=7.51, 6.56 Hz, 1H), 2.58 (bs, 1H), 2.19 (m, 1H), 1.47 (s, 3H), 1.36 (s, 3H). 13C NMR (68 MHz, CDC13) 6 130.74 (CH), 130.54 (CH), 108.67 (C), 81.40 (CH), 78.30 (CH), 71.61 (CH), 41.42 (CH=), 37.40 (CH), 35.10 (CH), 33.94 (CH2), 32.81 (CH1), 27.30 (CH3), 26.56 (CHz), 26.25 (CHz), 26.12 (CHa), 24.88 (CH3).

Examnle 10 (iR,2R,5R,68)-2-Cyclohexylmethyl-5,6-isopropylidenedioxycyclohex-3-en-l-ol (33): To a suspension of 350 mg (50.4 mmol) of lithium in 17 mL of ether at -30 C was added 1.395 mL (10.0 mmol) of cyclohexylmethyl bromide at -30 C. The mixture was stirred at -30 C for 2 h before it was cannulated to a suspension of 952 mg (5.00 mmol) of cuprous iodide in 5 mL of ether precooled to -40 C. The mixture was stirred at -40 C for 40 min and cooled to -78 C, when a solution of 279 mg (1.66 mmol) of 2b in 4 mL of THF was added. The resulting mixture was stirred at -78 C for 2 h before the reaction was quenched by 5 mL of saturated aqueous NH4C1 solution. The aqueous layer was extracted with ethyl acetate (3x15 mL), and the combined organic phases were dried over Na2SOe. Removal of solvent and column chromatography (silica gel, CH2C12/acetone, 5:1) afforded 165 mg (37%) of 33 and 25 mg (5%) of 32.

Example 11 (iR,2R,5R,6S)-5,6-Isopropylidenedioxy-2-methylcyclohex-3-en-l-ol (35): At -30 C methyllithium (2.55 mL, 3.57 mmol) was added slowly to a stirred suspension of cuprous iodide (340 mg, 1.78 mmol). =
After 30 min compound 2b (110 mg, 0.65 mmol) was added precooled by cannula at -78 C. The reaction was quenched after 30 min with saturated NH4C1 solution (10 mL). The mixture was extracted with CH2C12 (4x). The combined extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Chromatography (hexane/ethyl acetate, 67:33) afforded 35 (36 mg, 30%): colorless oil; 'H NMR (270 rn-Iz, CDC13) 6 5.85 (dd, J=10.0, 4.3 Hz, 1H) , 5.77 (ddd, J=10.0, 3.4 Fiz, 1H), 4.63 (dd, J=6.1, 3.4 Hz, 1H), 4.20 (dd, J=7.5, 6.2 Hz, 1H), 3.87 (dd, J=7.5, 4.7 Hz, 1H), 2.55 (m, 1H), 1.80 (s, 1H), 1.47 (s, 3H), 1.40 (s, 3H), 1.07 (d, J=7.3, 1H); 13C NMR (100.6 MHz, CDC13) b 3.35.13, 123.38, 109.03, 76.27, 72.12, 71.61, 33.30, 28.12, 25.87, 1.4.41.

Fxamnle 12 (iR,2R,5R,6S)-5,6-ISopropylidenedioxy-2-7phenylcyclohex-3-en-i-ol (36): To a degassed solution of compound 2b (200 mg, 1.19 mmol) in DMF (2.0 mL) and H10 (0.20 mL, 11 mmol) Pd(CH3CN)ZCla (15 mg, 0.058 mmol) was added under argon. After 5 min phenyltrimethyltin (344 mg, 1.43 mmol) was added to the orange solution which decolored to a pale yellow. The initially exothermic reaction was cooled to maintain rt. After 10 min more phenyltrimethyltin (160 mg) was added. After complete consumption of 2b (20 min) the black mixture was diluted (CH2C1õ 30 mL), filtered over Celite , washed (H201 brine), dried over Na2SO4, and concentrated in vacuo. Chromatography (hexane/ethyl acetate, 67:33) afforded 36 (29 mg, 10%): white solid;
mp. 95-96 C; IR (KBr)3490, 3090, 3040, 3000, 2940, 2880, 1495, 1455, 1382, 1370, 1250, 1160, 1070, 1055, 903, 880, 860, 800, 755, 705 cm';'H NMR (400 MHz, CDC13) b 7.36 (t, J=7.2 Hz, 2H), 7.29 (t, J=7.3 Hz, 1H), 7.25 (d, J=7.2 Hz, 2H), 603 (ddd, J=9.9, 3.7, 3.0 Hz, 1H), 5.88 (dt, J=9.9, 1.2 Hz, 1H), 4.73 (m, 1H), 4.17 (dd, J=8.8, 6.4 Hz, 1H), 3.62 (dt, J=1.2, 9.3 Hz, 1H), 3.28 (ddt, J=9.8, 2.8, 1.5 Hz, 1H), 2.06 (d, J=2.0 Hz, 1H), 1.53 (s, 3H), 1.42 (s, 3H); i3C
NMR (100.6 MHz, CDC13) 6 140.82, 134.61, 128.78 (2C), 128.38 (2C) 127.29, 124.17, 109.75, 79.02, 75.13, 72.74, 48.22, 28.33, 25.77; MS
(Cl+) m/z (rel. intensity) 231 (M'-15) (100), 171 (72), 159 (43), 143 (71), 128 (30), 115 (30), 101 (39), 91 (54).

F.XAII1nlP 13 (1R,2S,5R,6S)-N-(5,6-ISopropylidenedioxy-2,4-diphenyloyclohex-3-enyl)-(41-methylphanyl)sulfonamida (37): Phenyllithium (0.47 mL, 0.84 mmol) was added to a suspension ofCuI (80 mg, 0.42 mmol) in anhydrous THF at -40 C and stirred for 15 min._Compound 3a (50 mg, 0.14 mmol) in anhydrous THF (2 mL) was added precooledby cannula, followed by BF3Et2O (60 mg, 0.42 mmol), and the mixture was stirred and allowed to warm to rt over 12 h. The reaction was quenched using NH4OH solution, solid NHQC1 was added and the mixture was extracted with ether (5x). The combined extracts were washed with brine, dried over MgSO4 and concentrated i.n vacuo. Chromatography afforded 37 (35mg, 52%) : white solid; mp. 268-270 C: [a]p5 -105.2 (c=0.50, CHC13); 'H NMR (270 MHz, CDC13) 6 7.59 (m, 4H), 7.08-7.41 (m, lOH), 6.34 (d, J=4.8 Hz, 1H), 5.19 (d, J=5.7 Hz, 1H), 4.37 (d, J=6.6 Hz, 1H), 4.27 (dd, J=8.3, 5.5-Hz, 1H), 4.14 (t, J=5.1 Hz, 1H), 3.62 (ddd, J=8.1, 6.6, 5.2 Hz, 1H), 2.40 (s, 3H), 1.38 (s, 3H), 1.14 (s, 3H); 17C NMR (100.6 MHz, CDC13) 6 143.19 (C), 138.66 (C), 136.96 (C), 136.45 (C), 136.26 (C), 129.62 (2CH), 129.51 (2CH), 128.63 (2CH), 128.61 (2CH), 128.00 (CH), 127.35 (4CH), 125.97 (2CH), 109.56 (C), 74.21 (CH), 72.98 (CH), 55.26 (CH), 43.92 (CH), 27.28 (CH3), 25.95 (CHa), 21.45 (CH3); MS (CI+) m/z (rel. intensity) (M+H' not a/O 95135303 2193097 PCT/US95/07601 found), 418 (7), 400 (18), 247 (82), 222 (87), 139 (30), 98 (68), 91 (100).

ExamDle 14 (1R,SR,68)-1V-(4,4-Diphenyl-5,6-isopropylidenedioxycyclohex-2-enyl)-(41-methylphenyyl)sulfonamide (38): To a suspension of anhydrous CdCl2 (103 mg, 0.56 mmol) in anhydrous THF (10 mL) phenyllithium (0.62 mL, 1.12 mmol) was added slowly at rt, and the yellow solution was heated at reflux for 45 min. After cooling to rt compound 3a (100 mg; 0.28 mmol) in anhydrous THF (5 mL) was added and the mixture was heated to 55 C for 27 h. Saturated NH4C1 solution (15 mL) was added and the mixture was extracted with ether (4x). Drying over MgSOq, concentration in vacuo and chromatography (hexane/ethyl acetate, 80:20) afforded 38 (67 mg, 50%): glassy solid; 'H NMR (400 MHz, CDC13) b 7.65 (dm, J=8.4 Hz, 2H), 7.14-7.39 (m, 12H), 6.53 (dt, J'=9.9, 1.1 Hz, 1H), 5.82 (ddd, J=10.0, 5.4, 0.6 Hz, 1H), 5.07 (dd, J=6.1, 1.4 Hz, 1H), 4.37 (dd, J=6.1, 1.4 Hz, 1H), 3.87 (dd, J=9.3,5.3 Hz, 1H), 3.81 (d, J=9.3 Hz, 1H), 2.42 (s, 3H), 1.256 (s, 3H), 1.249 (s, 3H); i'C NMR (100.6 MHz, CDC13) 6 146.73 (C), 144.85 (C), 143.57 (C), 138.45 (CH), 138.03 (C), 129.82 (2CH), 129.20 (2CH), 129.02 (2CH), 127.93 (2CH), 127.80 (2CH), 127.55 (CH), 127.34 (2CH), 126.59 (CH), 126.40 (CH), 108.67 (C), 80.04 (CH), 78.57 (CH), 52.96 (CH), 50.80 (C), 26.94 (CH3), 25.22 (CH3), 21.76 (CH3) ; MS
(CI+) m%z (rel. intensity) (M+H' not found), 418 (14), 400 (12), 388 (10), 375 (12), 276 (22), 247 (100), 219 (45), 172 (23), 155 (28), 91 (100).

Examiple 15 (1R,2R,5R,6S)-N-[2,4-Di(cyclohexylmethyl)-5,6-isopropylidene-d.ioxycyclohex-3-eny1]-(4~-methylphenyl)sulfonamide (39): To a suspension of 193 mg (27.8 mmol) of lithium in 12 mL of ether cooled to -30 C was added 0.766 mL (5.56 mmol) of cyclohexylmethyl bromide.
The mixture was stirred at -30 C for 2 h and cannulated to a suspension of 529 mg (2.78 mmol) of cuprous iodide in 3 mL of ether precooled to -40 C. After the mixture was stirred at -40 C for 40 m.in, it was cooled to -78 C and a solution of 329 mg (0.92 mmol) of 3a in 5 mL of THF was added. The mixture was stirred at -78 C for 2 h, then slowly warmed to -40 C and stirred at -40 C for 2 h, then quenched with 5 mL of saturated aqueous ammoniumchloride and extracted with ethyl acetate (3x5 mL). The combinedorganic layers were dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed (silica gel, 4:1 hexane/EtOAc) to give 433 mg (89%) of 39.

White solid, mp 192-193 C; 'H NMR (270 MHz, CDC13) b 7.76 (d, J =8.30 Hz, 2H), 7.29 (d, J =8.09, 2H), 5.29 (bs, 1H), 4.46 (d, J =6.28 Hz, 1H), 4.40 (d, J=5.83 Hz, 1H), 4.28 (t, J =5.97 Hz, 1H), 3.38 (q, J
=4.51 Hz, 1H), 2.65 (bs, 1H), 2.41 (s, 3H), 2.11 (dd, J =14.26, 5.52 Hz, 1H), 1.82 (dd, J =14.15, 8.56 Hz, 1H), 1.31 (s, 3H), 1.14 (s, 3H), 0.50-1.72 (m, 24H). "C NMR (68 MHz, CDC13) 6 143.43 (C), 137.54 (C), 135.44 (C), 129.65 (2CH), 128.19 (CH), 127.39 (2CH), 109.28 (C), 75.01 (CH), 73.59 (CH), 55.06 (CH), 42.10 (CHz), 38.20 (CH2), 35.29 (CH), 34.55 (CH), 33.87 (CH=), 33.62 (CH2), 33.02 (2CH2), 32.06 (CH), 27.30 (CH3), 26.62 (2CH2), 26.26 (2CH2), 26.06 (CH2), 25.93 (CH3), 21.41 (CH3). Anal. Calcd for C30H4504NS:C, 69. 86; H, 8.79; N, 2.72. Found: C, 69.92; H, 8.81; N, 2.69._ Example 16 (1R,28,58,68)-N-(4-Chloro-5,6-isopropylidenedioxy-2-methylcyclohex-3-enyl)-(4'-methylphenyl)sulfonamide (40): To a suspension of Cu2 (14 mg, 0.073 mmol) in anhydrous ether was added a solution of methylmagnesium bromide (MeMgBr) (0.050 mL, 0.15 mmol) at -45 C and stirred for 30 min. Compound 3a (200 mg, 0.56 mmol) in anhydrous THF (5 mL) was added precooled via cannula and MeMgBr (0.40 mL, 1.20 mmol) was added over 60 min. After 7 h the white suspension was quenched using saturated NH4C1 solution (containing NH3, pH 9) (30 mL) and the mixture was extracted with ether (4x). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatography (toluene/ethyl acetate, 80:20) afforded 40 (111 mg, 53%) : 1H NMR (400 MHz, CDC13) 6 7.79 (dm, J=8.2 Hz, 2H), 7.29 (dm, J=8.7 Hz, 2H), 5.79 (d, J=3.0 Hz, 1H), 5.02 (d, J=8.5 Hz, 1H), 4.50 (dd, J=6.0, 1.4 Hz, 1H), 4.08 (dd, J=7.9, 6.0 Hz, 1H), 3.28 (q, J=8.0 Hz, 1H), 2.45 (s, 1H), 2.19 (ddquintett, J=1.4, 3.1, 7.3 Hz, 1H), 1.282 (s, 3H), 1.258 (s, 3H), 1.13 (d, J=7.2 Hz, 3H) ; "C NMR (100.6 MHz, CDC13) 6 143.2, 138.3, 132.1, 129.3 (2C), 128.4, 127.2 (2C), 110.3, 77.7, 75.2, 57.2, 36.5, 27.4, 25.8, 21.5, 18Ø

Rx mDl 97 (1R,48,5R,68)-N-(4-Cyclohexylmethyl-5,6-isopropylideae- ' =
dioxycyclohex-2-enyl)-(41-methylphenyl)sulfonamide (41): To a suspension of 187 mg (26.94 mmol) of lithium in 12 mL of ether at -WO 95135303 219 3 0 9 7 pCT/US95/07601 30 C was added 0.726 mL (5.20 mmol) of cyclohexylmethyl bromide at -30 C. The mixture was stirred at -30 C for 2 h before it was cannulated to a suspension of 495 mg (2.60 mmol) of cuprous iodide in 3 mL of ether precooled to -40 C. The mixture was stirred at -40 C for 40 min and cooled to -78 C, when a solution of 281 mg (0.87 mmol) of 3b in 4 mL of THF was added. The resulting mixture was stirred at -78 C for 2 h and then allowed to warm to -40 C before the reaction was quenched with 5 mL of saturated aqueous NHQC1 solution.
The aqueous layer was extracted with ethyl acetate (3x15 mL), and the combined organic phases were dried over Na2SO4. Removal of solvent and column chromatography (silica gel, hexane/ethyl acetate, 3:1) afforded 276 mg (76%) of 41.

White solid; mp 138-139 C; [a]p"=40.40 (c=0.96, CHC13) ; 'H NMR (270 MHz, CDC13) b 7.79 (d, J =8.25 Hz, 2H), 7.30 (d, J =8.21 Hz, 2H), 5.66 (m, 2H), 4.70 (d, J=5.58 Hz, 1H), 3.81 (m, 2H), 3.58 (m, 1H), 2.42 (s, 3H), 2.22 (bs, 1H), 1.23 (s, 3H), 1.16 (s, 3H), 0.71--1.80 (m, 13H) 13C NMR (68 MHz, CDC13) b 143.30 (C), 137'.48 (C), 132.34 (CH), 132.34 (CH), 129.49 (CH), 128.00 (CH), 127.51 (CH), 108.79 (C), 78.36 (CH), 78.18 (CH), 54.81 (CH), 41.74 (CH2), 37.03 (CH), 35.10 (CH), 33.80 (CH2), 32.99 (CH2), 27.24 (CH;), 26.55 (CHz), 26.23 (CH2), 25.19 (CH3), 21.30 (CH3).

Examnle 18 (1R,4R,SR,6S)-iV-(5,6-ISopropylidanadioxy-4-phanylcyclohex-2-enyl)-(4'-methylphenyl)sulfonsmide (42) and (7LR,2R,5R,6S)-N-(5,6-Isopropylidenedioxy-2-phanylcyclohex-3-enyl)-(4'-methylphenyl) sulfon-amide (43) Method A: With lithium diphenylcuprate: 2.36 mL of 1.8 M
phenyllithium solution was added slowly at -35 C to a suspension of 224 mg (1.18 mmol) of cuprous iodide in 8 mL of THF. The resulting mixture was stirred for 30 min, and a solution of 125 mg (0.39 mmol) of 3b in 2 mL of THF was added followed by 0.145 mL of BF3Et2O. The mixture was warmed over 5 h to rt with stirring, quenched with 5 mL
of saturated aqueous ammonium chloride solution and extracted with ethyl acetate (3x10 mL). The combined organic phases were dried over Na2SOõ removal of solvent and column chromatography afforded 54 mg (38%) of 42 and 10 mg (6%) of 43: white solid; mp. 165-167 C; 1H
NMR (270 MHz, CDC13) d 7.42 (dm, J=8.3 Hz, 2H), 7.26 (dm, J=8.3 Hz, 2H), 7.23 (m, 1H), 7.09 (m, 4H), 6.00 (ddd, J=9.9, 3.5, 2.7 Hz, 1H), WO 95/35303 21 9 3 0 9 Z. PCT/US95/076 1 5.87 (dt, J=9.9, 1.5 Hz, 1H), 4.67 (brt, J=4.7 Hz, 1H), 4.52 (d, J=8.2 Hz, iH), 4.14 (dd, J=9.0, 6.0 Hz, 1H), 3.65 (q, J=9.0 Hz, 1H), 3.24 (dq, J=8.6,1.9 Hz, 1H), 2.38 (s, 3H), 1.44 (s, 3H), 1.33 (s, 3H) ; 13C NMR (100.6 MHz, CDC13) b 142.4 (C), 140.1 (C), 138.6 (C), 134.6 (CH), 129.1 (2CH), 128.61 (2CH), 128.57 (2CH), 127.14 (CH), 126.96 (2CH), 124.2 (CH), 109.93 (C), 77.58 (CH), 72.16 (CH), 58.95 (CH), 47.70 (CH), 27.79 (CH3), 25.83 (CH3), 21.41 (CH3).

Method B: 43 with dilithium diphenylcyanocuprate: a suspension of 161 mg (1.80 mmol) of dry CuCN in 2 mL of_THF was treated with 2.0 mL of 1.8 M phenyllithium solution at -78 C. The mixture was warmed to -10 C with stirring to dissolve CuCN, and then cooled to -78'C, when a solution of 182 mg (0.57 mmol) of 3b was added, followed by 0.221 mL of_BF3Et,0. The mixture was stirred at -78 C for 3 h and then quenched with 5 mL of aqueous NHqCl solution (containing NH31 pH
8). After stirring at rt for 30 min, the mixture was extracted with ethyl acetate (3x15 mL), the combined organic layers were dried over Na2SO+ and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 10:1 CHC1,/acetone to give 52 mg (23%) of 43.

Examnle 19 43 and (iR,2R)-N-(6-Hydroxrycyclohexa-Z,4-dienyl)-(4"-methylphenyl)aulfonamide (24) with phenyltrimethyltin/Pd(0)-catalysis: To a degassed solution of compound 3b (80 mg, 0.249 mmol) in DMF (0.8 mL)/Hz0 (0.045 mL, 2.5 mmol, 10 eq.) Pd(CH3CN)ZClZ
(3.2 mg, 0.012 mmol) was added under argon. After 5 min phenyltrimethyltin (72 mg, 0.30 mmol) was added to the orange solution which decolored to a pale yellow. After 22 h and 37 h phenyltrimethyltin (2x72 mg) was added. When no more 3b remained the reaction mixture became black. After addition of 5-mL of water the mixture was extracted with ether (6x), dried over NazSOõ and concentrated. Chromatography (toluene/ethyl acetate, 80:20) afforded 43 (18.6 mg, 19%) and 24 (6.6 mg, 10%): colorless oil; 'H
NMR (270 MHz, CDC13) 6 7.78 (dm, J=8.3 Hz, 2H), 7.31 (dm, J=8.0 Hz, 2H), 5.85 (m, 3H), 5.43 (m, 1H), 5.34 (br.d, J=8.3 Hz, 1H), 4.42 (br.d, J=10.6 Hz, 1H), 4.00 (ddm, J=10.6, 8.3 Hz, 1H), 2.90 (br.s, 1H), 2.40 (s, 3H); 13C NMR (68 MHz, CDC13) 6 143.8 (C), 137.2 (C), 129.8 (2CH), 129.6 (CH), 127.2 (2CH), 126.5.(CH), 125.6 (CH), 124.0 (CH), 71.2 (CH), 57.1 (CH), 21.5 (CH3), ExamDle 20 (iR,2S,5R,68)-A7-(5,6-Isopropylidenedioxy-2-methylcyclohex-3-es{yl)-(4I-methylphenyi)sulfonamide (44): To a suspension of CuI (7 mg, 0.035 mmol) in anhydrous ether a solution of methylmagnesium bromide (MeMgBr) (0.025 mL, 0.075 mmol) was added at -45 C and stirred for 30 min. Compound 3b (113 mg, 0.35 mmol) in anhydrous THF (5 mL) was added precooled via cannula and MeMgBr (0.175 mL, 0.525 mmol) was added over 60 min. After 120 min saturated NH4Cl solution (containing NH3, pH 9) (30 mL) was added to the white suspension and the mixture was extracted with ether (4x). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. Chromatography (hexane/ethyl acetate, 80:20) afforded 44 (34 mg, 29%): white solid; mp. 112-113 C; [a]D20 -54.0 (c=0.58, CHC13):
114 (CHC13) 3260, 2980, 2930, 1450, 1375, 1320, 1150, 1080, 1060, 860, 805 cm'i; 'H NMR (270 MHz, CDC13) b 7.80 (dm, J=6.6 Hz, 2H), 7.28 (dm, J=7.9 Hz, 2H), 5.79 (ddd, J=10.0, 3.4, 2.4 Hz, 1H), 5.68 (ddd, J=10.9, 1.9, 0.8 Hz, 1H), 4.66 (d, J=8.7 Hz, iH), 4.52 (m, 1H), 3.92 (dd, J=8.0, 6.2 Hz, 1H), 3.17 (q, J=9.0 Hz, 1H), 2.41 (s, 314), 2.07 (m, 1H), 1.24 (s, 3H), 1.17 (s, 3H), 1.14 (d, J=7.2 Hz, 3H) ; i'C NMR (100.6 MHz, CDC13) 8 142.8 (C), 138.8 (C), 136.2 (CH), 129.2 (2CH), 127.3 (2CH), 122.9 (CH), 109.3 (C), 77.5 (CH), 72.2 (CH), 58.8 (CH), 35.75 (CH), 27.5 (CH3), 25.7 (CH3), 21.4 (CH3), 18.0 (CH;); MS (EI) m/z (rel. intensity) 337 (M') (1.5), 322 (6), 254 (45), 125 (98), 91 (100).

Claims (7)

WHAT IS CLAIMED

1. A method for preparing a compound which is a conjugate of units selected from cyclitols, carbohydrates and C-analogs thereo the method comprising:

coupling an epoxide of the formula:

wherein:
X' is H, halogen, CN, alkyl, aryl, or a heteroatom; and each R' is independently any suitable alcohol protecting group, provided that the R' at alcohol on C2 and C3 may be the same or different; or an aziridine of the formula:

wherein:
X" is H, halogen, CN, alkyl, aryl, or a heteroatom;
each R" is independently any alcohol protecting group, provided that the R" at alcohols on C2 and C3 may be the same or different; and R'" is H, CBZ, tosyl or any substituted or unsubstituted arylsulfonic acid amide, benzyl or CO2Me;

with a nucleophilic cyclitol, sugar or C-sugar having a nucleophilic carbonatom or heteroatom, resulting in the coupling of the epoxide or aziridine with the cyclitol, sugar or C-sugar via a ring opening reaction, thereby generating a nucleophilic group which is available for a further reaction.

2. A method of Claim 1 comprising coupling an epoxide of formula (2) wherein X' is H, Br, or Cl with a nucleophile being an organometallic reagent of the formula RM wherein R is methyl, methylcyclohexyl or phenyl; and M is Mg, Sn, Cu or Pd under suitable conditions.

3. A method of Claim 1 comprising coupling an aziridine of formula (3) wherein X" is H, Br, or Cl with a nucleophile being an organometallic reagent of the formula RM wherein R is methyl, methylcyclohexyl or phenyl; and M is Mg, Sn, Cu or Pd under suitable conditions.

4. A method of Claim 1 wherein the compound is GM3, sialyl Lewis X or a carbon or heteroatom conjugate or either.

5. A method of Claim 1 wherein the compound is a derivative of an epoxide of formula (2) or an aziridine of formula (3) and is selected from the group consisting of: (1R,2S,5S,6S)-(4-Chloro-5,6-isopropylidenedioxy-2-methylcyclohex-3-en-1-ol;
(1R,2S,5S,6S)-(4-Chloro-5,6-isopropylidenedioxy-2-cyclohexylmethylcyclohex-3-en-1-ol; (1R,2R,5R,6S)-2,4-Di(cyclohexylmethyl)-5,6-isopropylidenedioxy-cyclohex-3-en-1-ol; (1R,5R,6S)-5,6-Isopropylidenedioxy-4,4-diphenylcyclohex-2-en-1-ol; (1R,2S,5R,6S)-5,6-Isopropylidenedioxy-4-methylcyclohex-3-en-1-ol;
(1R,2S,SR,6S)-5,6-Isopropylidenedioxy-2-methylcyclohex-3-en-1-ol; (1R,4S,5R,6S)-4-Cyclohexylmethyl-5,6-isopropylidenedioxycyclohex-2-en-1-ol; (1R,2R,5R,6S)-2-Cyclohexylmethyl-5,6-isopropylidenedioxycyclohex-3-en-1-ol;
(1R,2R,5R,6S)-5,6-Isopropylidenedioxy-2-methylcyclohex-3-en-1-ol; (1R,2R,5R,6S)-5,6-Isopropylidenedioxy-2-phenylcyclohex-3-en-1-ol; (1R,2S,5R,6S)-N-(5,6-Isopropylidenedioxy-2,4-diphenylcyclohex-3-enyl)-(4'-methylphenyl)sulfonamide; (1R,5R,6S)-N-(4,4-Diphenyl-5,6-isopropylidenedioxycyclohex-2-enyl)-(4'-methylphenyl) sulfonamide; (1R,2R,5R,6S)-N-[2,4-Di(cyclohexylmethyl)-5,6-isopropylidene-dioxycyclohex-3-enyl]-4'-methylphenyl)sulfonamide; (1R,2S,5S,6S)-N-(4-Chloro-5,6-isopropylidenedioxy-2-methylcyclohex-3-enyl)-(4'-methylphenyl)sulfonamide; (1R,4S,5R,6S)-N-(4-Cyclohexylmethyl-5,6-isopropylidene-dioxycyclohex-2-enyl)-4'-methylphenyl)sulfonamide; (1R,4R,5R,6S)-N-(5,6-Isopropylidenedioxy-4-phenylcyclohex-2-enyl)-(4'-methylphenyl)sulfonamide; (1R,2R,5R,6S)-N-(5,6-isopropylidenedioxy-2-phenylcyclohex-3-enyl)-(4'-methylphenyl) sulfon-amide; (1R,2R)-N-(6-Hydroxycyclohexa-2,4-dienyl)-(4'-methylphenyl)sulfonamide; and (1R,2S,5R,6S)-N-(5,6-isopropylidenedioxy-2-methylcyclohex-3-enyl)-(4'-methylphenyl)sulfonamide.

6. A compound useful as a synthon, having the formula wherein:
X" is H, halogen, CN, alkyl, aryl, or a heteroatom;
each R" is independently any alcohol protecting group, provided that the R" at alcohols C2 and C3 may be the same or different; and R"' is H, CBZ, tosylamide or any substituted or unsubstituted arylsulfonic acid amide, benzyl or CO2Me.

7. The compound of Claim 6 which is selected from the group consisting of:
(1R,4S,5S,6R)-3-Chloro-4,5-isopropylidenedioxy-7-(4'-methyl-phenyl)sulfonylbicyclo[4.1.0]hept-2-ene;
(1R,4R,5S,6R)-3-Bromo-4,5-isopropylidenedioxy-7-(4'-methylphenyl)-sulfonylbicyclo[4.1.0]hept-2-ene; and 1R,4R,5S,6R)-4,5-Isopropylidenedioxy-7-(4'-methylphenyl) sulfonylbicyclo[4.1.0]hept-2-ene.